Changing strategies for treatment of systemic mycoses

There have been a number of changes in strategies in antifungal therapy in the past few years. AIDS related mycoses have decreased, and the increase of fluconazole resistant Candida albicans may be slowing because fewer severely immune depressed patients require constant fluconazole suppression. Candida species continue to be relatively common blood culture isolates. About half of these are C. albicans and half non-albicans species. In recent years, we have moved from the use of amphotericin B to fluconazole for initial treatment of candidemia. We have seen fluconazole resistant isolates emerge, primarily C. glabrata and a few C. krusei, but also C. albicans. It is unclear whether the increasing use of fluconazole in intensive care units will worsen this problem. There appears to be no advantage for the lipid formulations of amphotericin B, though they are useful to reduce or prevent renal toxicity. In the United States and Europe, prevention and treatment of aspergillosis have become increasingly important. There are increasing data suggesting that lipid formulations are more effective for both treatment and prevention of invasive disease in the most vulnerable patients with this infection. Renal toxicity is reduced but not avoided by use of the lipid formulations of amphotericin B. For those patients with less acutely progressing disease, the triazoles may be effective options. It is unclear at present whether itraconazole, voriconazole, or posaconazole will be the most favored drug. One promising new class, now in clinical trials, is the echinocandin group. Other agents, such as the sordarins, the chitin synthase inhibitors, and topoisomerase inhibitors, have promise but are much earlier in development. Unfortunately, we still have >50% treatment failure with acute invasive aspergillosis, and 20%-30% failures with candidemia. Now that we have multiple classes of antifungal drugs available, and others in preclinical trials, it would be advantageous to begin more active exploration of combination therapy with antifungals and with combined immune modulators and antifungals.